This proposal for a K08 Clinical Scientist Development Award entitled "A longitudinal study of HIV infection in Uganda," will allow Dr. Marcel E. Curlin, under the sponsorship of Dr. James I. Mullins and collaborators at the University of Washington and the Uganda Virology Research Center, to develop the skills necessary to pursue his long-term goals as an independent and highly productive physician-scientist in the field of HIV research. A complete understanding of the natural history of HIV-1 infection is lacking, but will be critical for our ability to effectively address the worldwide HIV epidemic. A clearer picture of the events in untreated HIV-1 infection is now emerging. Preliminary work suggests a pattern of evolution within the envelope gene of the HIV-1 genome (env) during the course of progressive infection characterized by early expansion of genetic diversity and divergence, followed by stabilization, and finally contraction of these parameters. These changes and the appearance of specific mutations encoding syncytium-inducing (SI) viral variants appear to herald the onset of AIDS. However, studies of viral evolution to date have been limited by narrow epidemiologic sampling, low statistical power, and intercurrent antiretroviral therapy, and most have involved only HIV-1 subtype B. Furthermore, attention has focused on the env gene, although evidence suggests that successful immune containment of disease depends critically on the interaction between host defenses and epitopes within the gag gene, and that the evolution of specific mutations in this gene may allow viral escape from immunity. It is now crucial to 1) establish a universal paradigm for evolutionary changes within env during HIV-1 infection across different viral subtypes, routes of infection, and host populations; 2) clarify the role of SI phenotype and viral subtype in progressive infection; and 3) extend our understanding of viral evolution to regions of the genome critical to an effective immune response. Our cohort of untreated individuals from Uganda followed over twelve years represents a unique opportunity to test the following hypotheses concerning the impact of viral diversity on pathogenesis in HIV: 1) Specific patterns of increase in env diversity, divergence and the appearance of SI phenotype predict the rate of disease progression. 2) Evolution of these changes is subtype dependent. 3) Evolution of mutations within the gag gene in the vicinity of epitopes important for effective immunity allows immune evasion and correlates with disease progression. These hypotheses will be tested by longitudinal sampling and phylogenetic analysis of viral genes in rapidly progressing and slowly progressing Ugandans infected with HIV-1 subtypes A and D.